Cyclin-dependent kinase inhibitor p27 as a mediator of the G1-S phase block induced by 1,25-dihydroxyvitamin D3 in HL60 cells

Qing Mei Wang, Jennifer B. Jones, George P. Studzinski

Research output: Contribution to journalArticlepeer-review

287 Scopus citations

Abstract

Progression of mammalian cells through G1 is controlled by the concerted action of protein kinases, the activities of which are modulated in both positive (cyclins) and negative [cyclin-dependent kinase inhibitors (CDIs)] manners by families of regulatory proteins. In differentiation of leukemia cells, a G1 arrest is a common, if not invariable, occurrence and takes place after the appearance of markers of monocytic differentiation in human leukemia HL60 cells treated with 1,25 dihydroxyvitamin D3 (1,25D3) at low to moderately high concentrations (F. Zhang et al., Cell Proliferation 27: 643-654, 1994). In the present study, we investigated the protein levels of several G1 regulatory proteins that are potential mediators of the 1,25D3- induced G1 block. During the first 24 h of exposure to a high concentration (4 x 10-7 M) of 1,25D3, no increase was noted in the immunodetectable levels of cyclins D1 or E, or CDIs p16(Ink4), p21(Clp1/Waf1), or p27(Kip1) even though monocytic differentiation markers were evident, and a prolongation of G1 was noted. After 48 h of exposure 4 x 10-7 M to 1.25D3, a G1 to S-phase block progressively increased in parallel with the abundance of the p27(Kip1) CDI. A transient increase in p21(Clp1/Waf1) was noted only at 48 hr. The increase in p27(Kip1) protein level was dependent on the concentration of 1,25D3 and was accompanied by an increase in cyclin D and E proteins, which normally peak in mid-G1 and at the G1 to S-phase transition, respectively. These results indicate that p27(Kip1) protein is a strong candidate for the cell cycle regulator that blocks the entry into the S-phase in 1,25D3-treated HL60 cells.

Original languageEnglish (US)
Pages (from-to)264-267
Number of pages4
JournalCancer Research
Volume56
Issue number2
StatePublished - Jan 15 1996

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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